Novel inhibitors of human glucose-6-phosphate dehydrogenase (HsG6PD) affect the activity and stability of the protein

Ramírez-Nava, Edson Jiovany; Hernández-Ochoa, Beatriz; Navarrete‐Vázquez, Gabriel; Arreguı́n-Espinosa, Roberto; Ortega-Cuéllar, Daniel; González‐Valdez, Abigail; Martínez‐Rosas, Víctor; Morales-Luna, Laura; Martínez-Miranda, Josué; Sierra-Palacios, Edgar; Rocha-Ramirez, Luz María; Franceschi, Lucia De; Marcial-Quino, Jaime; Gómez-Manzo, Saúl

doi:10.1016/j.bbagen.2020.129828

Cited by 6 publications

(11 citation statements)

References 32 publications

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“…Finally, it is interesting to mention that notwithstanding the fact that CNZ-3 and CNZ-7 compounds inhibited HpG6PD, they also inhibited the HsG6PD enzyme at high levels ( Supplementary Table S1 ), as previously reported by Ramírez-Nava et al [ 21 ]. Therefore, these compounds were not used in in silico studies as they did not show selective inhibition.…”

Section: Resultssupporting

confidence: 77%

“…Dr. Gabriel Navarrete-Vázquez from the Pharmacy Faculty of the Autonomous University of the State of Morelos provided the chemical compounds [ 32 ]. These compounds were selected based on the previously reported chemical inhibitors of human G6PD [ 21 ], prepared at a final concentration of 400 μM in 5% dimethyl sulfoxide (DMSO) (Sigma Aldrich, St. Louis, MO, USA), incubated with 0.2 mg/mL of HpG6PD (200 ng total) at 37 °C for two hours, and the HpG6PD residual activity was measured. In addition, the HpG6PD protein was incubated with 5% DMSO and used as a control.…”

Section: Methodsmentioning

confidence: 99%

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Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

et al. 2021

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Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC50 = 310, 465, 340, 204 and 304 μM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP+ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP+ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme’s active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori.

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Section: Resultssupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

et al. 2021

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“…These results indicated that inhibitors caused a rearrangement in the tryptophan residues' microenvironment, altering the protein's 3D structure, provoking a loss of catalytic activity. This same finding was reported in a G6PD study, in which a decrease in fluorescence intensity was observed when the human G6PD protein was incubated in the presence of CNZ-3 [19].…”

Section: Intrinsic and Extrinsic Fluorescence Assayssupporting

confidence: 88%

“…These results indicate that the four compounds caused changes in molar ellipticity (ϕ) at 222 nm (α-helix) and 208 nm (β-folded), revealing an increasing amount of random coil, which could explain the loss in catalytic activity. Despite the absence of studies of inhibitors of the fused TvG6PD::6PGL protein, similar findings have been observed over the human G6PD protein, in which compounds that affected catalytic activity also affected its secondary structure [19].…”

Section: Circular Dichroismsupporting

confidence: 55%

Kinetic and Molecular Docking Studies to Determine the Effect of Inhibitors on the Activity and Structure of Fused G6PD::6PGL Protein from Trichomonas vaginalis

et al. 2022

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Trichomoniasis is a sexually transmitted disease with a high incidence worldwide, affecting 270 million people. Despite the existence of a catalog of available drugs to combat this infection, their extensive use promotes the appearance of resistant Trichomonas vaginalis (T. vaginalis), and some side effects in treated people, which are reasons why it is necessary to find new alternatives to combat this infection. In this study, we investigated the impact of an in-house library comprising 55 compounds on the activity of the fused T. vaginalis G6PD::6PGL (TvG6PD::6PGL) protein, a protein mediating the first reaction step of the pentose phosphate pathway (PPP), a crucial pathway involved in the parasite’s energy production. We found four compounds: JMM-3, CNZ-3, CNZ-17, and MCC-7, which inhibited the TvG6PD::6PGL protein by more than 50%. Furthermore, we determined the IC50, the inactivation constants, and the type of inhibition. Our results showed that these inhibitors induced catalytic function loss of the TvG6PD::6PGL enzyme by altering its secondary and tertiary structures. Finally, molecular docking was performed for the best inhibitors, JMM-3 and MCC-7. All our findings demonstrate the potential role of these selected hit compounds as TvG6PD::6PGL enzyme selective inhibitors.

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“…Indeed, Compounds 6 and 9 are interesting bioactive compounds for the treatment of diabetes due to their antihyperglycemic effect. Further studies are needed to identify other possible targets in the body [46], in order to fully characterize its polypharmacological profile.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect

et al. 2021

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Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.

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Novel inhibitors of human glucose-6-phosphate dehydrogenase (HsG6PD) affect the activity and stability of the protein

Cited by 6 publications

References 32 publications

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

Kinetic and Molecular Docking Studies to Determine the Effect of Inhibitors on the Activity and Structure of Fused G6PD::6PGL Protein from Trichomonas vaginalis

Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect

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